The genetic basis of cancer dissemination, also known as metastasis, has been subject to intense debate. Metastasis genes have been identified as stress response genes, which in cancer are deregulated on the levels of aberrant expression and splicing.
Osteopontin is a cytokine that is frequently secreted by cancer cells and plays important roles in their ability to metastasize. Its expression is necessary and may be sufficient for invasiveness by breast tumors. Multiple metastatic breast cancer cell lines express osteopontin, and transfection of the osteopontin gene into benign tumorigenic human breast epithelial cell lines conveys invasive behavior. Increasing the expression of osteopontin, or transfection of osteopontin encoding cDNA into a previously benign cell line, is sufficient to produce a metastatic phenotype in a rat mammary model. High osteopontin levels in the plasma or tumor are an adverse prognostic factor in breast carcinoma.
Osteopontin derived from various cellular sources is heterogeneous and has been described previously, but the underlying biochemical processes of the heterogeneity are incompletely understood. Tumor-derived osteopontin was differentially detected by Western blotting and in a set of sandwich ELISA setups, characterized by using various antibody combinations. Distinctly sized osteopontin forms are secreted by tumor cells and their non-transformed counterparts. Cancer cells may secrete a splice variant that has a deletion in its N-terminal portion, for example, an osteosarcoma secreted a smaller form of osteopontin than the predominant product generated by non-transformed bone cells. Secretion of the smaller osteopontin form correlated with anchorage-independence, which may reflect a loss of adhesion to osteopontin, because in contrast to host osteopontin, tumor-derived osteopontin fails to associate with the extracellular matrix and remains soluble.
In humans, two osteopontin splice variants with deletions of exon 4 (termed osteopontin-c) or exon 5 (termed osteopontin-b) have been described and both variants are expressed in glioma cells. Differences in the physiologic roles between these variants have not been studied. Splice variants of osteopontin may be expressed selectively in malignant tumors and facilitate their dissemination. Functional alterations associated with the alternatively spliced exons may account for the observed differences between host and tumor osteopontin.